Emerging evidence highlights the importance of non-nicotine, sensorimotor factors (e.g., taste, aroma, handling) in cigarette addiction. Smokers prefer denicotinized cigarettes over i.v. pulses of nicotine, and blockade of the sensory aspects of smoking significantly reduces smoking satisfaction and reinforcement. Moreover, new treatments that address dependence on non-nicotine components of tobacco addiction have shown promise. Despite recent appreciation of non-nicotine, sensorimotor factors in cigarette addiction, little is known about the neurobiological basis of nicotine versus non-nicotine components of tobacco addiction. Thus, the broad objective of this research is to evaluate the neurobiological basis of nicotine and non-nicotine factors underlying cigarette addiction by systematically varying administration of these factors and measuring their effects on brain function using fMRI. In a fully factorial design, thirty-six (36) smokers will undergo imaging following 24 hrs of: 1) nicotine patch + smoking denicotinized [denic] cigarettes, 2) placebo patch + smoking denic cigarettes, 3) nicotine patch only, and 4) placebo patch only. Two tasks differentially sensitive to nicotine and non-nicotine factors a continuous working memory task (CWM) and a cue-reactivity task (CR), respectively will be completed. We hypothesize that abstinence from nicotine (regardless of smoking) will result in poorer CWM performance and decreased activation of the left dorsolateral prefrontal cortex (dlPFC); while abstinence from smoking and nicotine will result in greater abstinence-induced craving and increased activation in a network of cortical, limbic and striatal regions. Individual differences in self-reported smoking motivation and other smoking-related factors will predict the effects of nicotine and non-nicotine factors on brain functioning. In addition, a sample of 36 nonsmokers will also be scanned and smoker-nonsmoker group differences will be examined. The findings of this study will shed new light on the neurobiological basis of tobacco dependence and provide a framework for understanding individual differences in tobacco use, withdrawal and relapse. Moreover, it will provide basic science information that will aid in development of new and potentially more effective treatments that address both nicotine and non-nicotine components of smoking. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading cause of death and disability in the United States. There is a growing appreciation that factors other than nicotine contribute to the addictiveness of tobacco smoking. These include both sensory (taste, aroma) and behavioral (puffing, handling) factors. A better understanding of how these factors affect the brain can lead to new and more effective treatments to help smokers quit. [unreadable] [unreadable] [unreadable]